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WO2019041689A1 - Modèle de notation de gène imprimé pour les tumeurs colorectales et système composé de ce dernier - Google Patents

Modèle de notation de gène imprimé pour les tumeurs colorectales et système composé de ce dernier Download PDF

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WO2019041689A1
WO2019041689A1 PCT/CN2017/118956 CN2017118956W WO2019041689A1 WO 2019041689 A1 WO2019041689 A1 WO 2019041689A1 CN 2017118956 W CN2017118956 W CN 2017118956W WO 2019041689 A1 WO2019041689 A1 WO 2019041689A1
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imprinted
imprinted gene
genes
expression amount
gene
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成彤
周宁
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Lisen Imprinting Diagnostics Wuxi Co Ltd
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Lisen Imprinting Diagnostics Wuxi Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57419—Specifically defined cancers of colon
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis

Definitions

  • the present application relates to the field of biotechnology, and relates to the field of gene diagnosis, and in particular to a system for imprinting a gene-grading model for colorectal tumors and a composition thereof.
  • Colorectal cancer is a common malignant tumor in the digestive tract. The incidence rate is the third in all malignant tumors, and the mortality rate ranks fourth. About 1.2 million patients worldwide are diagnosed with colorectal cancer each year, and more than 600,000 patients die directly or indirectly from colorectal cancer. According to the World Health Organization (WHO), there were 774,000 cases of global colorectal cancer deaths in 2015. The incidence of colorectal cancer is lower in the age group under 45 years old, but it will increase with age. In recent years, the age of onset is younger.
  • WHO World Health Organization
  • stage I the 5-year survival rates of colorectal cancer patients with different stages in the United States were 90.1% (stage I), 69.2% (stage II and III), and 11.7% (stage IV), respectively, so colorectal cancer Early diagnosis and early treatment are very important. However, the early diagnosis rate of colorectal cancer is very low. The diagnosis rate of early intestinal cancer in the United States is about 25%, while the early diagnosis rate in China is only 10%. It is urgent to develop more sensitive and accurate detection methods.
  • Genomic imprinting is a way of gene regulation in epigenetics. It is characterized by methylation of alleles from a particular parent, such that one gene has only one allele and the other is in a state of gene silencing. This type of gene is called a blot (remember) gene. Deletion of the blot is an epigenetic change in which the allelic gene of the imprinted gene results in a silenced allele being activated and beginning to express the gene.
  • the methylation status of the imprinted gene can be used as a pathological marker to analyze the abnormal state of the cell by a specific molecular detection technique.
  • the analysis of molecular marker changes in colorectal cancer at the cellular level by imprinted gene detection technology can provide more accurate pre-diagnosis and diagnostic information, and has important guiding significance for the determination of the distance adjacent to the cancer during surgery.
  • the present application provides a system for imprinting gene grading models for colorectal tumors and a composition thereof for early visual observation of colorectal tissues at the cellular and tissue levels.
  • the change of the imprinted (marked) gene of cancer determines the degree of benign and malignant and malignant degree of colorectal cancer.
  • the present application provides an imprinted gene grading model for colorectal tumors by calculating the expression status of imprinted genes by changing the amount of imprinted gene expression and the abnormal expression level of imprinted gene copy number in colorectal cancer. Grading
  • the imprinting gene is any one or a combination of at least two of Z1, Z2, Z3 or Z4, the imprinting gene Z1 is Gnas, the imprinting gene Z2 is Igf2r, and the imprinting gene Z3 is Mest.
  • the imprinted gene is Plagl in Z4.
  • any one of Z1 - Z4 can be calculated, preferably Z1 and/or Z3, further preferably Z1.
  • the inventors found that the detection of a Z1 imprinted gene alone can achieve a sensitivity of 93.8% for colorectal cancer, and a Z2 imprinted gene alone can be diagnosed with a sensitivity of 47.9% for colorectal cancer.
  • a Z3 imprinted gene, the sensitivity of diagnosis of colorectal cancer can reach 83.3%, a Z4 imprinted gene alone, the sensitivity of diagnosis of colorectal cancer can reach 58.3%.
  • the combination may be a combination of Z1 and Z2, a combination of Z1 and Z3, a combination of Z1 and Z4, Z2 In combination with Z3, a combination of Z2 and Z4 or a combination of Z3 and Z4, preferably a combination of Z1 and Z3.
  • the inventors have found that by calculating the amount of the imprinted gene deletion expression of the two or more imprinted genes and the abnormal expression level of the imprinted gene copy number, the sensitivity can be further improved, and the combination of the two imprinted genes of the imprinted gene is detected.
  • the diagnostic sensitivity of colorectal cancer can reach more than 60%.
  • the sensitivity of diagnosis to colorectal cancer can reach 100%.
  • the combination of Z1 and Z4 can be sensitive to the diagnosis of colorectal cancer. More than 97.9%, the combination of Z1 and Z2, the sensitivity of diagnosis of colorectal cancer can reach more than 95.8%.
  • the imprinted gene grading model is most preferably a combination of detection Z1-Z4 genes.
  • the imprinted gene is deleted, after the cells are subjected to hematoxylin staining, there are two brown markers in the nucleus, and the abnormal copy number of the imprinted gene is that after the cells are subjected to hematoxylin staining, there are more than two brown markers in the nucleus.
  • the copy number abnormality is caused by abnormal gene replication of cancer cells, resulting in the expression of this gene as triploid or even higher polyploid.
  • the hematoxylin-stained label is selected from, but not limited to, brown, and staining with other colors can also be used for calculation of imprinted gene expression amount, imprinted gene deletion expression amount, and imprinted gene copy number abnormal expression amount.
  • the imprinted gene and the imprinted gene are simultaneously a concept, indicating the same meaning, and can be replaced.
  • the formula for calculating the expression level of the imprinted gene deletion and the abnormal expression amount of the imprinted gene copy is as follows:
  • Imprinted gene deletion gene expression level (LOI) c / (b + c + d) ⁇ 100%;
  • a is a cell nucleus in which there is no label in the nucleus and no imprinted gene is expressed in the cell after hematoxylin staining; and b is a brown mark in the nucleus after imprinting the cell with hematoxylin, and the cell nucleus in which the imprinted gene exists;
  • the c is a hematoxylin-stained cell, and two brown markers are present in the nucleus, and the nucleus of the imprinted gene is deleted;
  • the d is a hematoxylin staining of the cell, and there are two or more brown markers in the nucleus, and the imprinting gene copy number is abnormal.
  • the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount are divided into five different grades: the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the four imprinted genes for Z1-Z4 are respectively performed. Five different levels of division.
  • the five different levels of the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount for Z1 and Z3 are:
  • the imprinted gene Z1 and Z3 have an imprinted gene deletion expression amount of less than 15% and/or the imprinted genes Z1 and Z3 have an imprinted gene copy number abnormal expression amount of less than 0.8%;
  • the imprinted gene Z1 and Z3 have an imprinted gene deletion expression amount of 15-20% and/or the imprinted genes Z1 and Z3 have an abnormal expression amount of the imprinted gene copy number of 0.8-2.5%;
  • the imprinted gene Z1 and Z3 have an imprinted gene deletion expression amount of 20-30% and/or the imprinted genes Z1 and Z3 have an imprinted gene copy number abnormal expression amount of 2.5-3.5%;
  • the imprinted gene Z1 and Z3 have an imprinted gene deletion expression amount of 30-35% and/or the imprinted genes Z1 and Z3 have an imprinted gene copy number abnormal expression amount of 3.5-5%;
  • the imprinted gene deletion expression amount of the imprinted genes Z1 and Z3 is greater than 35% and/or the imprinted gene copy number abnormal expression amount of the imprinted genes Z1 and Z3 is greater than 5%.
  • the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the imprinted genes Z1 and Z3 are independent of each other.
  • the five different levels of the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount for Z2 and Z4 are:
  • the imprinted gene Z2 and Z4 have an imprinted gene deletion expression amount of less than 15% and/or the imprinted genes Z2 and Z4 have an imprinted gene copy number abnormal expression amount of less than 0.8%;
  • the imprinted gene Z2 and Z4 have an imprinted gene deletion expression amount of 15-20% and/or the imprinted genes Z2 and Z4 have an abnormal expression amount of the imprinted gene copy number of 0.8-1.5%;
  • the imprinted gene Z2 and Z4 have an imprinted gene deletion expression amount of 20-25% and/or the imprinted genes Z2 and Z4 have an imprinted gene copy number abnormal expression amount of 1.5-3%;
  • the imprinted gene Z2 and Z4 have an imprinted gene deletion expression amount of 25-30% and/or the imprinted genes Z2 and Z4 have an imprinted gene copy number abnormal expression amount of 3-5%;
  • the imprinted gene deletion expression amount of the imprinted genes Z2 and Z4 is greater than 30% and/or the imprinted gene copy number abnormal expression amount of the imprinted genes Z2 and Z4 is greater than 5%.
  • the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the imprinted genes Z2 and Z4 are independent of each other.
  • the present application provides a system for detecting the degree of benign and malignant colorectal tumors, comprising the following elements:
  • sampling unit obtaining a sample to be tested
  • Probe design unit design specific primers according to the imprinted gene sequence
  • the analysis unit determines the level of the imprinted gene deletion expression and the imprinted gene copy number abnormal expression level by calculating the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount by using the model described in the first aspect; The degree of benign and malignant colorectal tumors.
  • the imprinted gene is deleted, after the cells are subjected to hematoxylin staining, there are two brown-labeled nuclei in the nucleus, and the imprinting gene copy number abnormality is that after the cells are subjected to hematoxylin staining, there are two or more brown marks in the nucleus.
  • the copy number abnormality is caused by abnormal gene replication of cancer cells, resulting in the expression of this gene as triploid or even higher polyploid.
  • the hematoxylin-stained label is selected from, but not limited to, brown, and staining with other colors can also be used for calculation of imprinted gene expression amount, imprinted gene deletion expression amount, and imprinted gene copy number abnormal expression amount.
  • the detection system described in the present application is for early and intuitive observation of changes in the imprinted (spot) genes of colorectal tumors at the cellular and tissue levels to determine the benign and malignant degree of colorectal tumors, and to provide the most favorable for patients with early colorectal cancer. Treatment opportunities.
  • the sample to be tested described in the step (1) is derived from human tissues and/or cells.
  • the sample to be tested is feasible as long as the RNA is processed in a timely manner, and those skilled in the art can select according to the needs, and the sample to be tested includes the paraffin section of the tissue. And/or endoscopic screening of the sample, preferably endoscopic screening of the sample.
  • the specific operation procedure of the paraffin section of the tissue is to obtain a human tumor tissue sample, which is fixed in 10% neutral formalin in time, embedded in paraffin, cut into 10 ⁇ m thick, and made into a tissue film with a positively charged slide; Only 10 ⁇ m thick, so some of the microscopically seen nuclei are incomplete, so some false negative gene deletions will occur.
  • the specific operation procedure of the endoscope screening sample is to obtain suspicious tissue under the colorectal microscope, embedded in paraffin, cut into 10 ⁇ m thick, and obtained by using a positively charged slide to form a film.
  • the sampling process is simple, and the colorectal biopsy can be positioned compared to the blood circulation characteristics, and the colorectal biopsy has an experimental sample.
  • the imprinted gene is Z1-Z4, the imprinted gene Z1 is Gnas, the imprinted gene Z2 is Igf2r, the imprinted gene Z3 is Mest, and the imprinted gene is Plagl in Z4.
  • the imprinted genes Z1 (Gnas), Z2 (Igf2r), Z3 (Mest), and Z4 (Plagl1) are expressed in different degrees in normal tumor cell tissues, and expression levels and imprinting states are present when malignant lesions occur. There will be significant changes.
  • the designed probe is designed according to the imprinting genes Z1-Z4, namely Gnas, Igf2r, Mest and Plagl, and specifically selects a sequence as a probe in the endo-spin of each gene, and specifically selects the gene sequence.
  • the imprinting genes Z1-Z4 namely Gnas, Igf2r, Mest and Plagl, and specifically selects a sequence as a probe in the endo-spin of each gene, and specifically selects the gene sequence.
  • the location of specific genes are as follows:
  • the in situ hybridization employs an RNAscope in situ hybridization method.
  • the RNAscope in situ hybridization method uses a single or multi-channel colorimetric kit or a single or multi-channel fluorescent kit, preferably a single channel brown color kit or a multi-channel fluorescent kit.
  • the multi-channel coloring kit or the multi-channel fluorescent kit comprises two or more channels of coloring kits or fluorescent kits, and the two-channel coloring kit or multi-channel fluorescent reagent
  • the cassette can use two imprinted gene probes or a combination of imprinted genes and other genes to express even multiple imprinted genes and non-imprinted genes.
  • the formula for calculating the amount of expression of the imprinted gene and the amount of abnormal expression of the imprinted gene in the model is as follows:
  • Imprinted gene deletion gene expression level (LOI) c / (b + c + d) ⁇ 100%;
  • a is a cell nucleus in which there is no label in the nucleus and no imprinted gene is expressed in the cell after hematoxylin staining; and b is a brown mark in the nucleus after imprinting the cell with hematoxylin, and the cell nucleus in which the imprinted gene exists;
  • the c is a hematoxylin-stained cell, and two brown markers are present in the nucleus, and the nucleus of the imprinted gene is deleted;
  • the d is a hematoxylin staining of the cell, and there are two or more brown markers in the nucleus, and the imprinting gene copy number is abnormal.
  • the hematoxylin-stained label is selected from, but not limited to, brown, and staining with other colors can also be used for calculation of imprinted gene expression amount, imprinted gene deletion expression amount, and imprinted gene copy number abnormal expression amount.
  • the probe is amplified by in situ hybridization and Hemotoxy (hematoxylin) nuclear staining, and the presence of imprinted genes, imprinted gene deletions or copy number abnormalities in each nucleus is determined under a 40 ⁇ or 60 ⁇ microscope.
  • the degree of benign and malignant tumors of the sample is determined by calculating the gene expression amount of the imprinted gene deletion gene and the imprinted gene copy number abnormality. Since the section is only 10 microns, about 20% of the nuclei seen under the microscope are incomplete nuclei, which means that there is a possibility of partial false negatives.
  • the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount are divided into five different grades.
  • the five different grades are the division of the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the four imprinted genes for Z1-Z4, respectively.
  • the five different levels of the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount for Z1 and Z3 are:
  • the imprinted gene Z1 and Z3 have an imprinted gene deletion expression amount of less than 15% and/or the imprinted genes Z1 and Z3 have an imprinted gene copy number abnormal expression amount of less than 0.8%;
  • the imprinted gene Z1 and Z3 have an imprinted gene deletion expression amount of 15-20% and/or the imprinted genes Z1 and Z3 have an abnormal expression amount of the imprinted gene copy number of 0.8-2.5%;
  • the imprinted gene Z1 and Z3 have an imprinted gene deletion expression amount of 20-30% and/or the imprinted genes Z1 and Z3 have an imprinted gene copy number abnormal expression amount of 2.5-3.5%;
  • the imprinted gene Z1 and Z3 have an imprinted gene deletion expression amount of 30-35% and/or the imprinted genes Z1 and Z3 have an imprinted gene copy number abnormal expression amount of 3.5-5%;
  • the imprinted gene deletion expression amount of the imprinted genes Z1 and Z3 is greater than 35% and/or the imprinted gene copy number abnormal expression amount of the imprinted genes Z1 and Z3 is greater than 5%.
  • the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the imprinted genes Z1 and Z3 are independent of each other.
  • the five different levels of the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount for Z2 and Z4 are:
  • the imprinted gene Z2 and Z4 have an imprinted gene deletion expression amount of less than 15% and/or the imprinted genes Z2 and Z4 have an imprinted gene copy number abnormal expression amount of less than 0.8%;
  • the imprinted gene Z2 and Z4 have an imprinted gene deletion expression amount of 15-20% and/or the imprinted genes Z2 and Z4 have an abnormal expression amount of the imprinted gene copy number of 0.8-1.5%;
  • the imprinted gene Z2 and Z4 have an imprinted gene deletion expression amount of 20-25% and/or the imprinted genes Z2 and Z4 have an imprinted gene copy number abnormal expression amount of 1.5-3%;
  • the imprinted gene Z2 and Z4 have an imprinted gene deletion expression amount of 25-30% and/or the imprinted genes Z2 and Z4 have an imprinted gene copy number abnormal expression amount of 3-5%;
  • the imprinted gene deletion expression amount of the imprinted genes Z2 and Z4 is greater than 30% and/or the imprinted gene copy number abnormal expression amount of the imprinted genes Z2 and Z4 is greater than 5%.
  • the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the imprinted genes Z2 and Z4 are independent of each other.
  • the degree of benign and malignant colorectal tumors to be judged is classified into benign colorectal tumor, colorectal cancer potential, early colorectal cancer, mid-stage colorectal cancer, and advanced colorectal cancer.
  • the result of determining the degree of benign and malignant colorectal tumors is that the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the imprinted genes Z1, Z2, Z3 and Z4 are both smaller than the I grade, the imprinted gene Z1, and the imprinted gene Z1.
  • the imprinted gene deletion expression level of no more than one imprinted gene in Z2, Z3 and Z4 is grade I and the imprinted gene copy number of the imprinted genes Z1, Z2, Z3 and Z4 is not more than one imprinted gene.
  • the imprinted gene deletion expression level of the two imprinted genes of the grade or imprinted genes Z1, Z2, Z3 and Z4 is I grade and the abnormal expression amount of the imprinted gene copy number of the two imprinted genes is any of 0 grades In the case, it is a benign tumor;
  • the result of determining the degree of benign and malignant color of the colorectal tumor is that the imprinted gene of the two imprinted genes of the imprinted genes Z1, Z2, Z3 and Z4 has an imprinted gene whose expression level is one grade and the imprinted gene of one of the two imprinted genes
  • the copy number abnormal expression level is I
  • at least two imprinted genes of the imprinted genes Z1, Z2, Z3 and Z4 have at least two imprinted genes with imprinted gene expression level I and imprinted genes Z1, Z2, Z3 and Z4.
  • the imprinted gene copy number abnormal expression level is one of the class II or imprinted genes Z1, Z2, Z3 and Z4, and the imprinted gene deletion expression amount and the imprinted gene deletion expression amount are all of the II levels.
  • the situation is the potential of colorectal cancer;
  • the result of determining the degree of benign and malignant colorectal tumor is that the imprinted gene deletion expression level of at least two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is II, and at least at least one of the imprinting genes Z1, Z2, Z3 and Z4
  • the abnormal expression level of the imprinted gene copy number of the two imprinted genes is Grade II or the imprinted gene deletion expression amount and the imprinted gene deletion expression amount of the imprinted genes of Z1, Z2, Z3 and Z4 are both Grade III, then For early colorectal cancer;
  • the result of determining the degree of benign and malignant colorectal tumor is that the imprinted gene deletion expression level of at least two imprinted genes of the imprinted genes Z1, Z2, Z3 and Z4 is at least grade III, and at least at least one of the imprinted genes Z1, Z2, Z3 and Z4
  • the abnormal expression level of the imprinted gene copy number of the two imprinted genes is Grade III or the imprinted gene deletion expression amount and the imprinted gene deletion expression amount of the imprinted genes of Z1, Z2, Z3 and Z4 are both Grade IV, then For mid-stage colorectal cancer;
  • the result of determining the degree of benign and malignant colorectal tumor is that the imprinted gene deletion expression level of at least two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is at least grade IV or at least at least one of the imprinted genes Z1, Z2, Z3 and Z4
  • the abnormal expression level of the imprinted gene copy number of the two imprinted genes was grade IV, and it was advanced malignant colorectal cancer.
  • the present application provides the use of the model of the first aspect or the system of the second aspect in the manufacture of a medicament for detecting and/or treating colorectal cancer.
  • the colorectal cancer is detected to determine the degree of benign and malignant colorectal tumors, and the degree of benign and malignant colorectal tumors is divided into benign, colorectal cancer potential, early colorectal cancer, mid-stage colorectal cancer, and advanced colorectal cancer.
  • the result of determining the degree of benign and malignant colorectal tumors is that the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the imprinted genes Z1, Z2, Z3 and Z4 are less than grade I, the imprinted gene Z1, and the imprinted gene
  • the imprinted gene deletion expression level of no more than one imprinted gene in Z1, Z2, Z3, and Z4 is Grade I and the imprinted gene copy number abnormal expression amount of no more than one imprinted gene in the imprinted genes Z1, Z2, Z3, and Z4
  • the imprinted gene deletion expression level of the two imprinted genes of the class I or imprinted genes Z1, Z2, Z3 and Z4 is I and the abnormal expression amount of the imprinted gene copy number of the two imprinted genes is any of 0 In one case, it is a benign tumor;
  • the result of determining the degree of benign and malignant color of the colorectal tumor is that the imprinted gene deletion expression amount of the two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is I level and one of the two imprinted genes
  • the abnormal expression level of the imprinted gene copy number is I
  • the imprinted gene deletion expression level of at least 3 imprinted genes of the imprinted genes Z1, Z2, Z3 and Z4 is I grade and at least 2 of the imprinted genes Z1, Z2, Z3 and Z4
  • the imprinted gene copy number abnormal expression level of the imprinted gene is I or the imprinted gene, and the imprinted gene deletion expression amount and the imprinted gene deletion expression amount of the imprinted genes Z1, Z2, Z3 and Z4 are all in the second level. In one case, it is the potential of colorectal cancer;
  • the result of determining the degree of benign and malignant color of the colorectal tumor is that the imprinted gene deletion expression level of at least two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is II, and the imprinting genes Z1, Z2, Z3 and Z4
  • the abnormal expression level of the imprinted gene copy number of at least 2 imprinted genes is Grade II or the imprinted gene deletion expression amount and the imprinted gene deletion expression amount of the imprinted genes Z1, Z2, Z3 and Z4 are both grade III. , is early colorectal cancer;
  • the result of determining the degree of benign and malignant colorectal tumor is that the imprinted gene deletion expression level of at least two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is grade III, and the imprinting genes Z1, Z2, Z3 and Z4
  • the abnormal expression level of the imprinted gene copy number of at least 2 imprinted genes is Grade III or the imprinted gene deletion expression amount and the imprinted gene deletion expression amount of the imprinted genes Z1, Z2, Z3 and Z4 are both Grade IV , is a mid-stage colorectal cancer;
  • the result of determining the degree of benign and malignant color of the colorectal tumor is that the imprinted gene deletion expression level of at least two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is IV or the imprinting genes Z1, Z2, Z3 and Z4
  • the abnormal expression level of the imprinted gene copy number of at least two imprinted genes is grade IV, and it is advanced malignant colorectal cancer.
  • the detection model and system described in the present application visually express the performance of the imprinted deletion on the sample of the colorectal cancer patient, and objectively, intuitively, earlyly and accurately detect the in situ labeling of the imprinted gene.
  • the imprinting (trace) gene changes and can provide a quantitative model that makes a significant contribution to the diagnosis of colorectal tumors;
  • the detection system of the present application can determine the degree of benign and malignant colorectal tumors before surgery in patients with colorectal cancer, thereby providing a basis for surgery and precision treatment, which is a revolutionary breakthrough in the diagnosis of colorectal tumors in the field of cell molecules. ;
  • This application can accurately determine the type of colorectal tumor.
  • the sensitivity of detection of samples with malignant potential above the level is 93.8%; if combined with detection of Z1 and Z3 probes, above the malignant potential Graded sample detection sensitivity can be increased to 100%, greatly improving the early stage of colorectal cancer, and clear diagnosis, especially for early screening and postoperative follow-up of cancer, especially for follow-up of suspected relapsed patients. Time, making a significant contribution to saving the lives of patients;
  • This application can detect the benign and malignant tissues of adjacent tissues, and can provide guidance for the determination of the distance adjacent to the cancer during surgery to ensure complete resection of the diseased tissue and greatly reduce the recurrence rate of the patient;
  • the detection method of the present application is different from the immunohistochemical method, which reduces false positives and other negative effects, and not only the target of silencing, culling, rearrangement of the gene by the deletion site of the imprinted gene associated with the colorectal tumor found. To the drug or technical method, it can be used to guide the later treatment and medication.
  • 1 is a pathological section of colorectal cancer in a hematoxylin-stained nuclei in an embodiment of the present application, wherein the a is a hematoxylin-stained cell, and there is no label in the nucleus, and the imprinted gene is not expressed; After hematoxylin staining, there is a brown mark in the nucleus, and the imprinted gene exists; the c is the hematoxylin staining of the cells, there are two brown marks in the nucleus, and the imprinted gene is deleted; the d is the cell nucleus after hematoxylin staining There are more than two brown marks in memory, and the imprinted gene copy number is abnormal;
  • Fig. 2(a) shows the expression status of four genes in the pathological section of grade 0 colorectal cancer
  • Fig. 2(b) shows the expression status of four genes in the pathological section of grade I colorectal cancer
  • Fig. 2(c) is The expression status of four genes in the pathological section of grade II colorectal cancer
  • Fig. 2(d) shows the expression status of four genes in the pathological section of grade III colorectal cancer
  • Fig. 2(e) shows the grade IV colorectal cancer.
  • Fig. 3(a) shows the intensity of imprinting deletion of 4 genes for colorectal cancer
  • Fig. 3(b) shows the intensity of copy number abnormality of 4 genes for colorectal cancer
  • LOI is the amount of imprinted gene deletion gene expression
  • CNV is the gene expression amount of abnormal copy number of imprinted gene
  • Figure 4 (a) shows the intensity of the imprinted gene Z1 imprint deletion and copy number abnormality
  • Figure 4 (b) shows the intensity of the imprinted gene Z2 imprint deletion and copy number abnormality
  • Figure 4 (c) shows the imprinted gene Z3 imprint deletion and copy number.
  • the intensity of the abnormality is the intensity of the imprinting gene Z4 imprint deletion and copy number abnormality
  • LOI is the imprinted gene deletion gene expression level
  • CNV is the gene expression amount of the imprinted gene copy number abnormality
  • Fig. 5(a) shows the distribution range and grading standard of imprinted gene and Z1 in 73 cases of colorectal cancer pathological sections
  • Fig. 5(b) shows the imprinted gene Z2 applied to 73 cases of colorectal cancer pathology.
  • the distribution range and grading standard of imprinting deletion and copy number abnormality shows the distribution range and grading standard of imprinting deletion and copy number abnormality in 73 pathological sections of colorectal cancer with imprinting gene Z3.
  • 5(d) is the imprinting gene Z4 applied to 73 cases of colorectal cancer pathological sections, the distribution range and grading standard of imprinting deletion and copy number abnormality
  • LOI is the imprinting gene deletion gene expression level
  • CNV is the imprinting gene copy number abnormal gene The amount of expression.
  • the method for detecting the imprinted gene comprises the following steps:
  • tissue cells of colorectal cancer cut into 10 ⁇ m thick, and fixed in 10% neutral formalin solution to prevent RNA degradation, fixed time is 24 hours, paraffin embedding (FFPE), The slide needs to be loaded with a positive charge, and the slice is baked in an oven at 40 ° C for more than 3 hours;
  • FFPE paraffin embedding
  • Design probe design specific primers according to the imprinted gene sequence
  • the designed probe is designed according to the imprinting genes Z1 (Gnas), Z2 (Igf2r), Z3 (Mest) and Z4 (Plagl1), and specifically selects a sequence as a probe in the inner loop of each gene, and specifically selects
  • Z1 Gas
  • Z2 Igf2r
  • Z3 Mest
  • Z4 Plagl1
  • the formula for calculating the amount of expression of the imprinted gene and the amount of abnormal expression of the imprinted gene in the model is as follows:
  • Imprinted gene deletion gene expression level (LOI) c / (b + c + d) ⁇ 100%;
  • a, b, c, and d are as shown in FIG. 1 , wherein a is a cell nucleus in which no hemoglobin is stained in the nucleus and the imprinted gene is not expressed; and b is a hematoxylin staining of the cell.
  • a is a cell nucleus in which no hemoglobin is stained in the nucleus and the imprinted gene is not expressed; and b is a hematoxylin staining of the cell.
  • a brown mark in the nucleus to imprint the nucleus of the gene There is a brown mark in the nucleus to imprint the nucleus of the gene
  • the c is the hematoxylin staining of the cell, there are two brown marks in the nucleus, and the nucleus of the imprinted gene is deleted
  • the d is the cell nucleus after hematoxylin staining
  • the nuclei with abnormal copy number of the imprinted gene are imprinted.
  • the colorectal biopsy sample was obtained by taking a suspicious lesion under a colorectal microscope, fixed in a 10% neutral formalin solution for 24 hours, embedded in paraffin (FFPE), and cut into 10 micron thick sections.
  • FFPE paraffin
  • Fig. 4(a)-Fig. 4(d) The sensitivity of each imprinted gene to colorectal cancer is shown in Fig. 4(a)-Fig. 4(d).
  • the deletion and copy number abnormality of imprinted gene Z1 appear at the earliest stage of colorectal cancer lesions, in malignant potential and early stage The stage of rectal cancer was significantly increased; the imprinted gene Z2 was less sensitive in the early stage of colorectal cancer lesions, and some copy number abnormalities occurred in the malignant potential stage, but did not continue to rise in the early and middle stages of colorectal cancer, and the imprinted deletion occurred in the late stage.
  • Tissues from 73 patients with colorectal cancer including colorectal biopsy samples (10 micron), were obtained in the same manner as in Example 1.
  • the imprinted gene deletion expression amount is less than 15% and/or the imprinted gene copy number abnormal expression amount is less than 0.8%, and the imprinted gene deletion expression amount is 15- 20% and/or imprinted gene copy number abnormal expression level is 0.8-2.5% for grade I, imprinted gene deletion expression level is 20-30% and/or imprinted gene copy number abnormal expression level is 2.5-3.5% for grade II, The imprinted gene deletion expression amount is 30-35% and/or the imprinted gene copy number abnormal expression level is 3.5-5% for the grade III, the imprinted gene deletion expression amount is greater than 35% and/or the imprinted gene copy number abnormal expression amount is greater than 5%.
  • Grade IV is
  • the imprinted gene deletion expression amount is less than 15% and/or the imprinted gene copy number abnormal expression amount is less than 0.8%, and the imprinted gene deletion expression amount is 15- 20% and/or imprinted gene copy number abnormal expression level is 0.8-1.5% for grade I, imprinted gene deletion expression level is 20-25% and/or imprinted gene copy number abnormal expression level is 1.5-3% for grade II,
  • the amount of imprinted gene deletion is 25-30% and/or the abnormal expression of imprinted gene copy number is 3-5% to grade III, the imprinted gene deletion expression is greater than 30% and/or the imprinted gene copy number is abnormally expressed by more than 5%.
  • Grade IV is
  • the imprinted gene deletion expression amount is less than 15% and/or the imprinted gene copy number abnormal expression amount is less than 0.8%, and the imprinted gene deletion expression amount is 15- 20% and/or imprinted gene copy number abnormal expression level is 0.8-2.5% for grade I, imprinted gene deletion expression level is 20-30% and/or imprinted gene copy number abnormal expression level is 2.5-3.5% for grade II, The imprinted gene deletion expression amount is 30-35% and/or the imprinted gene copy number abnormal expression level is 3.5-5% for the grade III, the imprinted gene deletion expression amount is greater than 35% and/or the imprinted gene copy number abnormal expression amount is greater than 5%.
  • Grade IV is
  • the imprinted gene deletion expression amount is less than 15% and/or the imprinted gene copy number abnormal expression amount is less than 0.8%, and the imprinted gene deletion expression amount is 15- 20% and/or imprinted gene copy number abnormal expression level is 0.8-1.5% for grade I, imprinted gene deletion expression level is 20-25% and/or imprinted gene copy number abnormal expression level is 1.5-3% for grade II,
  • the amount of imprinted gene deletion is 25-30% and/or the abnormal expression of imprinted gene copy number is 3-5% to grade III, the imprinted gene deletion expression is greater than 30% and/or the imprinted gene copy number is abnormally expressed by more than 5%. It is level IV.
  • the result of judging the degree of benign and malignant colorectal tumors is that the imprinted gene deletion expression amount and the imprinted gene copy number abnormal expression amount of the imprinted genes Z1, Z2, Z3 and Z4 are less than grade I, and the imprinted genes Z1, Z2, Z3 and Z4
  • the imprinted gene deletion expression level of no more than one imprinted gene is grade I and the imprinted gene copy number of no more than one imprinted gene in the imprinted genes Z1, Z2, Z3 and Z4 is abnormally expressed in grade I or imprinted gene Z1
  • the imprinting gene deletion expression level of the two imprinted genes in Z2, Z3, and Z4 is Grade I and the abnormal expression level of the imprinted gene copy number of the two imprinted genes is in any of the 0 grades, and is benign Tumor
  • the result of determining the degree of benign and malignant color of the colorectal tumor is that the imprinted gene of the two imprinted genes of the imprinted genes Z1, Z2, Z3 and Z4 has a deletion gene expression level of I and an imprinted gene copy of one of the two imprinted genes
  • the number of abnormal expression levels is I, and the imprinting gene of at least 3 imprinting genes in the imprinting genes Z1, Z2, Z3, and Z4 is deleted at a level I and the imprinting genes Z1, Z2, Z3, and Z4 are at least 2 imprinted genes.
  • the abnormal expression level of the imprinted gene copy number is one of the grade II or the imprinted gene of the imprinted genes Z1, Z2, Z3 and Z4, and the imprinted gene deletion expression amount and the imprinted gene deletion expression amount are all in the second level. Then judge the potential of colorectal cancer;
  • the result of determining the degree of benign and malignant colorectal tumors is that the imprinted gene deletion expression level of at least two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is II, and at least 2 of the imprinted genes Z1, Z2, Z3 and Z4
  • the imprinted gene copy number abnormal expression level of the imprinted gene is Grade II or the imprinted gene deletion expression amount and the imprinted gene deletion expression amount of the imprinted gene of Z1, Z2, Z3 and Z4 are both Grade III, then Early colorectal cancer;
  • the result of determining the degree of benign and malignant color of the colorectal tumor is that the imprinted gene deletion expression level of at least two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is III, and at least 2 of the imprinted genes Z1, Z2, Z3 and Z4
  • the imprinted gene copy number abnormal expression level of the imprinted gene is III or the imprinted gene deletion expression amount and the imprinted gene deletion expression amount of the imprinted gene Z1, Z2, Z3 and Z4 are both IV, then Mid-stage colorectal cancer;
  • the result of determining the degree of benign and malignant colorectal tumors is that the imprinted gene deletion expression level of at least two imprinted genes in the imprinted genes Z1, Z2, Z3 and Z4 is IV or at least 2 of the imprinted genes Z1, Z2, Z3 and Z4
  • the imprinted gene copy number abnormal expression level of the imprinted gene is grade IV, which is advanced colorectal cancer.
  • the detection model and system described in the present application visually express the performance of the imprinted deletion on the sample of the colorectal cancer patient, and the method of in situ labeling of the imprinted gene is objective, intuitive, early, and accurate.
  • the change in the imprinted (trace) gene is detected and a quantitative model can be provided to make a significant contribution to the diagnosis of colorectal tumors.

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Abstract

La présente invention concerne un modèle de notation de gène imprimé pour les tumeurs colorectales et un système composé de ce dernier, le modèle notant le changement d'un gène imprimé dans les tumeurs colorectales à l'aide du calcul de la quantité d'expression de la délétion de gène imprimé et la quantité d'expression des nombres de copies de gènes imprimés anormaux, le gène imprimé étant n'importe lequel ou une combinaison d'au moins deux de Z1, Z2, Z3, ou Z4, le gène imprimé Z1 étant Gnas, le gène imprimé Z2 étant Igftr, le gène imprimé Z3 étant Mest, et le gène imprimé Z4 étant Plagl1.
PCT/CN2017/118956 2017-08-31 2017-12-27 Modèle de notation de gène imprimé pour les tumeurs colorectales et système composé de ce dernier Ceased WO2019041689A1 (fr)

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